The role of solitary chemosensory cells in periodontal homeostasis

孤立化学感应细胞在牙周稳态中的作用

• 批准号: 10614064
• 负责人: Robert F. Margolskee
• 金额: $ 51.99万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614064
• 关键词: Adult; Affect; Age; Air; Alveolar Bone Loss; Anti-Bacterial Agents; Atherosclerosis; Bacteria; Bacterial Infections; Cells; Cycloheximide; Cytoprotection; Dendritic Cells; Diabetes Mellitus; Disease; Elderly; Elements; Epithelial Attachment; Epithelium; Gene Expression; Gingiva; Goals; Grant; Growth; Health; Heterogeneity; Homeostasis; Immune; Immunity; Immunohistochemistry; Impairment; In Situ Hybridization; In Vitro; Inflammation; Inflammatory; Innate Immune Response; Knock-out; Knockout Mice; Lactones; Ligands; Liquid substance; Lymphoid Cell; Macrophage; Mediator; Microbe; Mucous Membrane; Mus; Natural Immunity; Oral; Oral health; Pathway interactions; Periodontal Diseases; Periodontitis; Population; Receptor Cell; Research; Rheumatoid Arthritis; Risk; Risk Factors; Role; Science; Sensory; Sentinel; Signal Pathway; Signal Transduction; Signaling Molecule; Systemic disease; Taste Buds; Taste Perception; Testing; Tissues; Tooth Loss; Tooth structure; Topical application; Wild Type Mouse; Work; alveolar bone; alveolar destruction; antimicrobial peptide; bone; bone loss; chemokine; cytokine; disability; dysbiosis; experimental study; homoserine lactone; knockout gene; microbial; microbiome composition; mouse model; novel strategies; oral bacteria; oral microbial community; oral microbiome; pathogen; prevent; protective effect; quorum sensing; receptor; response; selective expression; taste transduction; transcriptomics

Project Summary Periodontal disease, which results from bacterial infection and inflammation of the gums and bone that surround and support the teeth, affects nearly half of US adults over 30, with ~9% having severe periodontitis. The hallmark of periodontitis is destruction of alveolar bone, resulting ultimately in extended tooth loss and oral disability. Periodontitis is a major oral health problem, particularly among the elderly, that increases the risk for systemic diseases, including atherosclerosis, rheumatoid arthritis, and diabetes mellitus. The general goals of this grant are to determine the role of newly discovered gingival solitary chemosensory cells (gSCCs) in protecting against periodontitis, to identify the receptors, signaling pathways and effectors involved in innate immunity evoked by gSCC activation, and to identify compounds that activate gSCCs to harness host innate immunity to reduce periodontitis. Periodontitis results from polymicrobial dysbiosis, which perturbs the ecologically balanced oral microbiota, and from disruption of the host innate immunity, which also contributes to the destruction of periodontal tissue. While much is known about how microbes and host immunity contribute to periodontitis, it is still unclear which gingival cells protect against the disease. Recent studies in several types of mucosae have identified taste cell-like SCCs as specialized chemosensitive sentinel cells that detect bacteria and evoke host innate immune responses. Most recently, we have identified gSCCs in the mouse gingival junctional epithelium that is part of the epithelial barrier protecting against bacterial infection of the tooth and surrounding gingiva. gSCCs express bitter taste receptors along with other taste transduction components, respond to bacterial signaling molecules, and trigger intrinsic innate immunity to protect against periodontitis. The experiments of this proposal study the role of gSCCs in gingival/tooth health to determine if gSCCs evoke innate immune responses that prevent overgrowth of oral bacteria in the gingival mucosa (Aim 1); identify the receptors and signaling components of gSCCs and the mechanism by which gSCCs promote gingival release of antimicrobial peptides and inflammatory cytokines (Aim 2); and determine if “on demand “activation of the gSCC signaling pathway reduces periodontitis (Aim 3). Understanding the initiating receptors and underlying mechanisms of these responses may lead to new approaches to promote oral health and treat periodontitis.

项目概要 牙周病，由细菌感染以及牙龈和骨骼炎症引起， 包围和支撑牙齿，影响近一半 30 岁以上的美国成年人，其中约 9% 患有严重牙周炎。 牙周炎的特点是牙槽骨遭到破坏，最终导致牙齿长期脱落和口腔溃疡。 牙周炎是一个主要的口腔健康问题，尤其是老年人，它增加了患牙周病的风险。 全身性疾病，包括动脉粥样硬化、类风湿性关节炎和糖尿病。 这笔赠款旨在确定新发现的牙龈孤立化学感应细胞（gSCC）在 预防牙周炎，识别参与先天性牙周炎的受体、信号通路和效应子 gSCC 激活引起的免疫，并鉴定激活 gSCC 来利用宿主先天性的化合物 免疫力，减少牙周炎。 牙周炎是由多种微生物失调引起的，它扰乱了口腔的生态平衡 微生物群，以及宿主先天免疫的破坏，这也有助于破坏 虽然人们对微生物和宿主免疫如何导致牙周炎了解很多，但目前尚不清楚。 最近对几种类型粘膜的研究仍不清楚哪些牙龈细胞可以预防这种疾病。 鉴定出味觉细胞样 SCC 作为专门的化学敏感前哨细胞，可检测细菌并唤起宿主 先天免疫反应。 最近，我们在小鼠牙龈交界上皮中发现了 gSCC，该上皮是牙龈连接上皮的一部分。 上皮屏障可防止牙齿和周围牙龈的细菌感染。 苦味受体与其他味觉传导成分一起响应细菌信号分子， 并触发内在的先天免疫来预防牙周炎。 gSCC 在牙龈/牙齿健康中的作用，以确定 gSCC 是否会引起先天免疫反应，从而预防 牙龈粘膜中口腔细菌的过度生长（目标 1）； gSCC 以及 gSCC 促进抗菌肽和牙龈释放的机制 炎症细胞因子（目标 2）；并确定 gSCC 信号通路是否“按需”激活 减少牙周炎（目标 3）。 这些反应可能会带来促进口腔健康和治疗牙周炎的新方法。

项目成果

Oral Microbiota-Host Interaction Mediated by Taste Receptors.

味觉感受器介导的口腔微生物群与宿主的相互作用

• DOI: 10.3389/fcimb.2022.802504
• 发表时间: 2022
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7

Mouse Mandibular Retromolar Taste Buds Associated With a Mucus Salivary Gland.

小鼠下颌磨牙后味蕾与粘液唾液腺相关。

• DOI: 10.1093/chemse/bjab019
• 发表时间: 2021
• 期刊: Chemical senses
• 影响因子: 3.5
• 作者: Nguyen,QuanT;BeckCoburn,GraceE;Valentino,Amber;Karabucak,Bekir;Tizzano,Marco
• 通讯作者: Tizzano,Marco